Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene

Okada, Y and Diogo, D and Greenberg, JD and Mouassess, F and Achkar, WAL and Fulton, RS and Denny, JC and Gupta, N and Mirel, D and Gabriel, S and Li, G and Kremer, JM and Pappas, DA and Carroll, RJ and Eyler, AE and Trynka, G and Stahl, EA and Cui, J and Saxena, R and Coenen, MJH and Guchelaar, HJ and Huizinga, TWJ and Dieudé, P and Mariette, X and Barton, A and Canhão, H and Fonseca, JE and De Vries, N and Tak, PP and Moreland, LW and Bridges, SL and Miceli-Richard, C and Choi, HK and Kamatani, Y and Galan, P and Lathrop, M and Raj, T and De Jager, PL and Raychaudhuri, S and Worthington, J and Padyukov, L and Klareskog, L and Siminovitch, KA and Gregersen, PK and Mardis, ER and Arayssi, T and Kazkaz, LA and Plenge, RM (2014) Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene. PLoS ONE, 9 (2).

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Abstract

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10-6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. © 2014 Plenge et al.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Okada, Y Diogo, D Greenberg, JD Mouassess, F Achkar, WAL Fulton, RS Denny, JC Gupta, N Mirel, D Gabriel, S Li, G Kremer, JM Pappas, DA Carroll, RJ Eyler, AE Trynka, G Stahl, EA Cui, J Saxena, R Coenen, MJH Guchelaar, HJ Huizinga, TWJ Dieudé, P Mariette, X Barton, A Canhão, H Fonseca, JE De Vries, N Tak, PP Moreland, LW lwm5@pitt.edu LWM5 Bridges, SL Miceli-Richard, C Choi, HK Kamatani, Y Galan, P Lathrop, M Raj, T De Jager, PL Raychaudhuri, S Worthington, J Padyukov, L Klareskog, L Siminovitch, KA Gregersen, PK Mardis, ER Arayssi, T Kazkaz, LA Plenge, RM
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Sawalha, Amr H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	10 February 2014
Date Type:	Publication
Journal or Publication Title:	PLoS ONE
Volume:	9
Number:	2
DOI or Unique Handle:	10.1371/journal.pone.0087645
Schools and Programs:	School of Medicine > Medicine
Refereed:	Yes
Date Deposited:	18 Jun 2014 20:04
Last Modified:	22 Jun 2021 15:55
URI:	http://d-scholarship.pitt.edu/id/eprint/21907

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